Pathophysiological Concepts in Cardiovascular Medicine: Update 2026.

Abstract

Cardiovascular disease remains the leading cause of death worldwide, yet classification still relies largely on anatomy, hemodynamics, and function, which can group patients with different underlying disease biology. Human studies across cardiovascular conditions now identify vascular, myocardial, metabolic, renal, hematologic, and peripheral processes that modify disease expression beyond conventional labels. Atherogenic particle burden, lipoprotein(a), clonal hematopoiesis, myocardial energetic and genetic abnormalities, chamber remodeling, dysfunctional adiposity, iron deficiency, skeletal muscle dysfunction, and cancer-associated cardiac wasting illustrate how similar phenotypes can arise from different substrates. These observations are supported to varying degrees by genetic, longitudinal, imaging, physiological, tissue, and interventional evidence, and their relative importance differs across patients and disease stages. Association with disease severity or outcome should therefore not be interpreted automatically as causal or therapeutically modifiable. Longitudinal phenotyping can clarify temporal relationships, while mechanistic studies should establish target engagement and the expected biological or physiological response. Clinical outcome trials must then determine whether modifying a candidate pathway improves patient-relevant outcomes. Mechanistically informed phenotyping may complement established cardiovascular classification by refining patient selection, distinguishing clinically meaningful substrates from associated signals, and supporting mechanism-directed therapeutic development where the evidence is sufficiently robust, rather than replacing established clinical disease labels.